Selenium Dihalides Click Chemistry: Highly Efficient Stereoselective Addition to Alkynes and Evaluation of Glutathione Peroxidase-Like Activity of Bis(E-2-halovinyl) Selenides

Highly efficient stereoselective syntheses of novel bis(E-2-chlorovinyl) selenides and bis(E-2-bromovinyl) selenides in quantitative yields by reactions of selenium dichloride and dibromide with alkynes were developed. The reactions proceeded at room temperature as anti-addition giving products exclusively with (E)-stereochemistry. The glutathione peroxidase-like activity of the obtained products was estimated and compounds with high activity were found. The influence of substituents in the products on their glutathione peroxidase-like activity was discussed.


Introduction
The term "click chemistry" was coined by K. Barry Sharpless, in 1998 and was first fully described by Sharpless, Kolb, and Finn in 2001 [1]. They believe that click chemistry reactions must be wide in scope, give very high yields, and generate only inoffensive byproducts. The required process characteristics include simple reaction conditions, readily available starting materials and reagents, high selectivity and atom economy, and simple product isolation by non-chromatographic methods. The authors also included sulfenyl halides addition reactions to carbon-carbon multiple bonds to the click chemistry [1]. Although selenenyl halides additions were not mentioned, the chemical properties of these reagents are very similar to those of sulfenyl halides, but addition reactions of selenenyl halides often proceed with higher selectivity [2][3][4][5][6].
The main methods for preparation of vinyl selenides are based on electrophilic addition of organylselenenyl halides to the triple bond as well as on nucleophilic addition of selenolate or selenide anions to acetylenes. Previously convenient methods for preparation of divinyl selenide and alkyl vinyl selenides from elemental selenium and acetylene were developed at this institute [27][28][29]. Unsubstituted divinyl selenide (1) was obtained in 80% yield from elemental selenium and acetylene in an aqueous solution of potassium  (1) in 80% yield from elemental selenium and acetylene at 105-115 °C for 15 h (3 days, 5 h heating every day) under acetylene pressure in an autoclave.
The synthesis of resveratrol and its derivatives was realized in several stages from vinyl selenides [30]. Resveratrol and its methoxylated analogues are well known compounds due to the fact of their anti-inflammatory, anticancer, antibacterial and neuroprotective activity [30]. In addition, the cross-coupling reaction of vinyl selenides with terminal alkynes in the presence of a nickel/CuI catalyst at room temperature leading to (Z)-and (E)-enyne derivatives in good yields with retention of stereochemical configuration is very important [31]. Vinyl selenides, which exhibit antinociceptive [39], hepatoprotective [40], and antioxidant [41] activity, were found.
The synthesis of resveratrol and its derivatives was realized in several stages from vinyl selenides [30]. Resveratrol and its methoxylated analogues are well known compounds due to the fact of their anti-inflammatory, anticancer, antibacterial and neuroprotective activity [30]. In addition, the cross-coupling reaction of vinyl selenides with terminal alkynes in the presence of a nickel/CuI catalyst at room temperature leading to (Z)-and (E)-enyne derivatives in good yields with retention of stereochemical configuration is very important [31]. Vinyl selenides, which exhibit antinociceptive [39], hepatoprotective [40], and antioxidant [41] activity, were found.
The synthesis of resveratrol and its derivatives was realized in several stages from vinyl selenides [30]. Resveratrol and its methoxylated analogues are well known compounds due to the fact of their anti-inflammatory, anticancer, antibacterial and neuroprotective activity [30]. In addition, the cross-coupling reaction of vinyl selenides with terminal alkynes in the presence of a nickel/CuI catalyst at room temperature leading to (Z)-and (E)-enyne derivatives in good yields with retention of stereochemical configuration is very important [31]. Vinyl selenides, which exhibit antinociceptive [39], hepatoprotective [40], and antioxidant [41] activity, were found.
The organoselenium heterocyclic compound, ebselen, shows neuroprotective, antiinflammatory, cytoprotective, and glutathione peroxidase-like properties [58][59][60][61][62][63]. Ebselen is used medicinally as an anti-inflammatory agent as well as for prevention of cardiovascular diseases and ischemic stroke. Furthermore, preliminary studies demonstrate that ebselen shows promising inhibitory activity against COVID-19 in cell-based assays [59]. The effect was attributed to irreversible inhibition of the main protease via a covalent bond formation with the thiol group of the active center's cysteine (Cys-145). The organoselenium heterocyclic compound, ebselen, shows neuroprotective, anti-inflammatory, cytoprotective, and glutathione peroxidase-like properties [58][59][60][61][62][63]. Ebselen is used medicinally as an anti-inflammatory agent as well as for prevention of cardiovascular diseases and ischemic stroke. Furthermore, preliminary studies demonstrate that ebselen shows promising inhibitory activity against COVID-19 in cell-based assays [59]. The effect was attributed to irreversible inhibition of the main protease via a covalent bond formation with the thiol group of the active center's cysteine (Cys-145).
The reaction of selenium dibromide with 2-butyne, 3-hexyne, 4-octyne, and 5-decyne was realized in a similar manner. Selenium dibromide was produced by mixing elemental selenium and a solution of bromine in methylene chloride or chloroform. After dissolution of the selenium, the obtained solution of selenium dibromide was added dropwise to a solution of dialkylacetylene in methylene chloride or chloroform, and the reaction mixture was stirred for 1-3 h at room temperature. After removing the solvent from the reaction mixture by a rotary evaporator, the residue was dried in vacuum giving bis(E-2-bromovinyl) selenides 8-11 (quantitative yields), which did not require additional purification. The reaction proceeded in a stereoselective mode as anti-addition affording products only with (E)-configuration (Scheme 5).
furyl chloride and immediately involved in further reactions (Scheme 4). Removing the solvent from the reaction mixture followed by drying in vacuum led to pure products 4-7 in quantitative yields.
The reaction of selenium dibromide with 2-butyne, 3-hexyne, 4-octyne, and 5-decyne was realized in a similar manner. Selenium dibromide was produced by mixing elemental selenium and a solution of bromine in methylene chloride or chloroform. After dissolution of the selenium, the obtained solution of selenium dibromide was added dropwise to a solution of dialkylacetylene in methylene chloride or chloroform, and the reaction mixture was stirred for 1-3 h at room temperature. After removing the solvent from the reaction mixture by a rotary evaporator, the residue was dried in vacuum giving bis(E-2-bromovinyl) selenides 8-11 (quantitative yields), which did not require additional purification. The reaction proceeded in a stereoselective mode as anti-addition affording products only with (E)-configuration (Scheme 5). Divinyl selenide 1 was obtained by a modified procedure in 91% yield from elemental selenium and acetylene in an aqueous solution of potassium hydroxide and hydrazine hydrate at 70-80 °C for 5 h under acetylene pressure in an autoclave (Scheme 6). The isolation of the target product did not require organic solvents for extraction: the organic phase was simply separated from the reaction mixture by a separatory funnel. This method of carrying out the reaction in water without using organic solvents can be considered as a "green chemistry method". This procedure is superior to the earlier method [27,28] in the yield of the target product, the duration (5 h instead of 15 h, 3 days) and the temperature of the process (70-80 °C instead of 105-115 °C).
Selenide 1 was used for the glutathione peroxidase-like activity studies, and its activity was compared with that of bis(2-halovinyl) selenides 4-11.
The glutathione peroxidase-like activity of the obtained products was estimated using the model reaction of dithiothreitol oxidation by tert-butyl hydroperoxide (Scheme 7) in the presence of a catalytic number of synthesized compounds as a catalysts (10% mol) [14,[47][48][49][50][51]. The progress of this reaction was monitored by 1 H NMR spectroscopy at room temperature (dithiothreitol, 0.07 mmol; tert-butyl hydroperoxide, 0.07 mmol; tested product, 0.007 mmol; deuterochloroform/CD3CD = 95/5, 0.5 mL). The control experiment was conducted under the same reaction conditions but in the absence of the catalyst. Divinyl selenide 1 was obtained by a modified procedure in 91% yield from elemental selenium and acetylene in an aqueous solution of potassium hydroxide and hydrazine hydrate at 70-80 • C for 5 h under acetylene pressure in an autoclave (Scheme 6). solvent from the reaction mixture followed by drying in vacuum led to pure products 4-7 in quantitative yields.
The reaction of selenium dibromide with 2-butyne, 3-hexyne, 4-octyne, and 5-decyne was realized in a similar manner. Selenium dibromide was produced by mixing elemental selenium and a solution of bromine in methylene chloride or chloroform. After dissolution of the selenium, the obtained solution of selenium dibromide was added dropwise to a solution of dialkylacetylene in methylene chloride or chloroform, and the reaction mixture was stirred for 1-3 h at room temperature. After removing the solvent from the reaction mixture by a rotary evaporator, the residue was dried in vacuum giving bis(E-2-bromovinyl) selenides 8-11 (quantitative yields), which did not require additional purification. The reaction proceeded in a stereoselective mode as anti-addition affording products only with (E)-configuration (Scheme 5). Divinyl selenide 1 was obtained by a modified procedure in 91% yield from elemental selenium and acetylene in an aqueous solution of potassium hydroxide and hydrazine hydrate at 70-80 °C for 5 h under acetylene pressure in an autoclave (Scheme 6). The isolation of the target product did not require organic solvents for extraction: the organic phase was simply separated from the reaction mixture by a separatory funnel. This method of carrying out the reaction in water without using organic solvents can be considered as a "green chemistry method". This procedure is superior to the earlier method [27,28] in the yield of the target product, the duration (5 h instead of 15 h, 3 days) and the temperature of the process (70-80 °C instead of 105-115 °C).
Selenide 1 was used for the glutathione peroxidase-like activity studies, and its activity was compared with that of bis(2-halovinyl) selenides 4-11.
The glutathione peroxidase-like activity of the obtained products was estimated using the model reaction of dithiothreitol oxidation by tert-butyl hydroperoxide (Scheme 7) in the presence of a catalytic number of synthesized compounds as a catalysts (10% mol) [14,[47][48][49][50][51]. The progress of this reaction was monitored by 1 H NMR spectroscopy at room temperature (dithiothreitol, 0.07 mmol; tert-butyl hydroperoxide, 0.07 mmol; tested product, 0.007 mmol; deuterochloroform/CD3CD = 95/5, 0.5 mL). The control experiment was conducted under the same reaction conditions but in the absence of the catalyst. The isolation of the target product did not require organic solvents for extraction: the organic phase was simply separated from the reaction mixture by a separatory funnel. This method of carrying out the reaction in water without using organic solvents can be considered as a "green chemistry method". This procedure is superior to the earlier method [27,28] in the yield of the target product, the duration (5 h instead of 15 h, 3 days) and the temperature of the process (70-80 • C instead of 105-115 • C).
Selenide 1 was used for the glutathione peroxidase-like activity studies, and its activity was compared with that of bis(2-halovinyl) selenides 4-11.
The glutathione peroxidase-like activity of the obtained products was estimated using the model reaction of dithiothreitol oxidation by tert-butyl hydroperoxide (Scheme 7) in the presence of a catalytic number of synthesized compounds as a catalysts (10 mol%) [14,[47][48][49][50][51]. The progress of this reaction was monitored by 1 H NMR spectroscopy at room temperature (dithiothreitol, 0.07 mmol; tert-butyl hydroperoxide, 0.07 mmol; tested product, 0.007 mmol; deuterochloroform/CD 3 CD = 95/5, 0.5 mL). The control experiment was conducted under the same reaction conditions but in the absence of the catalyst. It was found that unsubstituted divinyl selenide 1 showed the best activity a the tested selenides (Figure 1). The activity of bis(2-bromovinyl) selenides, in ge exceeds the activity of bis(2-chlorovinyl) selenides (Figures 1 and 2). This trend explained in terms of electron density on the selenium atom in divinyl sel bis(2-chlorovinyl) selenides, and bis(2-bromovinyl) selenides. We suppose that th tron density on the selenium atom and the presence of electron-withdrawing g which are in conjugation with double bonds and an unshared electron pair of th Scheme 7. The model reaction of dithiothreitol oxidation by tert-butyl hydroperoxide in the presence of a catalytic number of synthesized compounds as catalysts (10 mol%).
It was found that unsubstituted divinyl selenide 1 showed the best activity among the tested selenides (Figure 1). The activity of bis(2-bromovinyl) selenides, in general, exceeds the activity of bis(2-chlorovinyl) selenides (Figures 1 and 2). This trend can be explained in terms of electron density on the selenium atom in divinyl selenide, bis(2chlorovinyl) selenides, and bis(2-bromovinyl) selenides. We suppose that the electron density on the selenium atom and the presence of electron-withdrawing groups, which are in conjugation with double bonds and an unshared electron pair of the selenium atom, can affect redox processes and manifestation of the glutathione peroxidase-like activity. Since bromine and especially chlorine are electronegative atoms, they can decrease the electron density on the selenium atom in bis(2-chlorovinyl) selenides and bis(2-bromovinyl) selenides. The chlorine atom was superior to the bromine atom in electronegativity and the glutathione peroxidase-like activity of bis(2-bromovinyl) selenides exceeded the activity of chloro-containing selenides (Figures 1 and 2). Unsubstituted divinyl selenide does not have electronegative heteroatoms, and it showed the best activity among the tested selenides.
ence of a catalytic number of synthesized compounds as catalysts (10% mol).
It was found that unsubstituted divinyl selenide 1 showed the best activity among the tested selenides (Figure 1). The activity of bis(2-bromovinyl) selenides, in general, exceeds the activity of bis(2-chlorovinyl) selenides (Figures 1 and 2). This trend can be explained in terms of electron density on the selenium atom in divinyl selenide, bis(2-chlorovinyl) selenides, and bis(2-bromovinyl) selenides. We suppose that the electron density on the selenium atom and the presence of electron-withdrawing groups, which are in conjugation with double bonds and an unshared electron pair of the selenium atom, can affect redox processes and manifestation of the glutathione peroxidase-like activity. Since bromine and especially chlorine are electronegative atoms, they can decrease the electron density on the selenium atom in bis(2-chlorovinyl) selenides and bis(2-bromovinyl) selenides. The chlorine atom was superior to the bromine atom in electronegativity and the glutathione peroxidase-like activity of bis(2-bromovinyl) selenides exceeded the activity of chloro-containing selenides (Figures 1 and 2). Unsubstituted divinyl selenide does not have electronegative heteroatoms, and it showed the best activity among the tested selenides.  Another trend, which can be seen based on the obtained data (Figures 1 and 2), was the increase in glutathione peroxidase-like activity with the increasing length of the carbon skeleton in tested molecules. However, in the case of 5-decyne derivatives 7 and 11, XC(Bu) = C(Bu)SeC(Bu) = C(Bu)X, the activity decreased and was lower than the ac- Another trend, which can be seen based on the obtained data (Figures 1 and 2), was the increase in glutathione peroxidase-like activity with the increasing length of the carbon skeleton in tested molecules. However, in the case of 5-decyne derivatives 7 and 11, XC(Bu) = C(Bu)SeC(Bu) = C(Bu)X, the activity decreased and was lower than the activity of 4-octyne derivatives 6 and 10, XC(Pr) = C(Pr)SeC(Pr) = C(Pr)X (Figures 1 and 2). We assume that the steric factor begins to manifest itself in the latter case, and the selenium atom in the 5-decyne derivative becomes sterically less accessible for redox processes.
It is worth noting that this is the first example of glutathione peroxidase-like activity assessment of divinyl selenide and bis(2-halovinyl) selenides, which do not contain additional heteroatoms.
Bis(2-chlorovinyl) and bis(2-bromovinyl) selenoxides were supposed to be intermediates in the catalytic process of oxidation of dithiothreitol by tert-butyl hydroperoxide on the assessment of glutathione peroxidase-like activity of the corresponding selenides.
The efficient syntheses of novel families of bis(2-chlorovinyl) selenoxides 12-15 (Scheme 8) and bis(2-bromovinyl) selenoxides 16-19 (Scheme 9) in 95-99% yields by oxidation of corresponding selenides with sodium metaperiodate or tert-butyl hydroperoxide were developed. The application of sodium metaperiodate for the oxidation of the selenides made it possible to obtain cleaner products in comparison with the use of tert-butyl hydroperoxide. Another trend, which can be seen based on the obtained data (Figures 1 and 2), was the increase in glutathione peroxidase-like activity with the increasing length of the carbon skeleton in tested molecules. However, in the case of 5-decyne derivatives 7 and 11, XC(Bu) = C(Bu)SeC(Bu) = C(Bu)X, the activity decreased and was lower than the activity of 4-octyne derivatives 6 and 10, XC(Pr) = C(Pr)SeC(Pr) = C(Pr)X (Figures 1 and 2). We assume that the steric factor begins to manifest itself in the latter case, and the selenium atom in the 5-decyne derivative becomes sterically less accessible for redox processes.
It is worth noting that this is the first example of glutathione peroxidase-like activity assessment of divinyl selenide and bis(2-halovinyl) selenides, which do not contain additional heteroatoms.
Bis(2-chlorovinyl) and bis(2-bromovinyl) selenoxides were supposed to be intermediates in the catalytic process of oxidation of dithiothreitol by tert-butyl hydroperoxide on the assessment of glutathione peroxidase-like activity of the corresponding selenides.
The efficient syntheses of novel families of bis(2-chlorovinyl) selenoxides 12-15 (Scheme 8) and bis(2-bromovinyl) selenoxides 16-19 (Scheme 9) in 95-99% yields by oxidation of corresponding selenides with sodium metaperiodate or tert-butyl hydroperoxide were developed. The application of sodium metaperiodate for the oxidation of the selenides made it possible to obtain cleaner products in comparison with the use of tert-butyl hydroperoxide. As a rule, compounds with a sulfur−selenium bond are considered as intermediates in the oxidation reactions of thiols by peroxides catalyzed by organoselenium compounds [14,[47][48][49][50][51]. In our case, the following scheme can be proposed to explain the catalytic effect of the obtained compounds (Scheme 10). The reaction of the formed selenoxides with dithiothreitol is assumed to lead to the heterocyclic intermediate, which undergoes conversion to the oxidized form of dithiothreitol with regeneration of the catalyst. As a rule, compounds with a sulfur−selenium bond are considered as intermediates in the oxidation reactions of thiols by peroxides catalyzed by organoselenium compounds [14,[47][48][49][50][51]. In our case, the following scheme can be proposed to explain the catalytic effect of the obtained compounds (Scheme 10). The reaction of the formed selenoxides with dithiothreitol is assumed to lead to the heterocyclic intermediate, which undergoes conversion to the oxidized form of dithiothreitol with regeneration of the catalyst.
Thus, stereoselective syntheses of novel bis(E-2-chlorovinyl)selenides and bis(E-2bromovinyl)selenides in quantitative yields by electrophilic addition reactions of selenium dichloride and selenium dibromide to dialkylacetylenes were developed. The glutathione peroxidase-like activity of the obtained products was estimated and compounds with high activity were found.
As a rule, compounds with a sulfur−selenium bond are considered as intermediates in the oxidation reactions of thiols by peroxides catalyzed by organoselenium compounds [14,[47][48][49][50][51]. In our case, the following scheme can be proposed to explain the catalytic effect of the obtained compounds (Scheme 10). The reaction of the formed selenoxides with dithiothreitol is assumed to lead to the heterocyclic intermediate, which undergoes conversion to the oxidized form of dithiothreitol with regeneration of the catalyst. Thus, stereoselective syntheses of novel bis(E-2-chlorovinyl)selenides and bis(E-2-bromovinyl)selenides in quantitative yields by electrophilic addition reactions of selenium dichloride and selenium dibromide to dialkylacetylenes were developed. The glutathione peroxidase-like activity of the obtained products was estimated and compounds with high activity were found.

General Information
The 1 Н (400.1 MHz) and 13 C (100.6 MHz) NMR spectra (see Supplementary Materials) were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in CDCl3 solutions and referred to the residual solvent peaks of CDCl3 (δ = 7.27 and 77.16 ppm in 1 H-and 13 C-NMR, respectively). Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). The organic solvents were dried and distilled according to standard procedures.

Scheme 10.
A proposed catalytic cycle to explain the catalytic effect of the obtained compounds.

General Information
The 1 H (400.1 MHz) and 13 C (100.6 MHz) NMR spectra (see Supplementary Materials) were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in CDCl 3 solutions and referred to the residual solvent peaks of CDCl 3 (δ = 7.27 and 77.16 ppm in 1 H-and 13 C-NMR, respectively). Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). The organic solvents were dried and distilled according to standard procedures.
Bis(E-2-chloro-1-methyl-1-propenyl) selenide (4). A solution of selenium dichloride (1 mmol) in methylene chloride (2 mL) was added dropwise to a solution of 2-butyne (108 mg, 2 mmol) in methylene chloride (18 mL). The mixture was stirred for 1 h at room temperature. The solvent was removed by a rotary evaporator and the residue was dried in vacuum giving compound 4 (258 mg) as a light yellow oil in quantitative yield. 1  Bis(E-2-chloro-1-propyl-1-pentenyl) selenide (6) was obtained under the same conditions as compound 4 but during 2 h from selenium dichloride and 4-octyne as a light yellow oil in quantitative yield. 1  Bis(E-2-chloro-1-butyl-1-hexenyl) selenide (7) was obtained under the same conditions as compound 4 but for 2 h from selenium dichloride and 5-decyne as a light yellow oil in quantitative yield. 1  Bis(E-2-bromo-1-methyl-1-propenyl) selenide (8). A solution of selenium dibromide (1 mmol) in methylene chloride (2 mL) was added dropwise to a solution of 2-butyne (108 mg, 2 mmol) in methylene chloride (18 mL). The mixture was stirred for 1 h at room temperature. The solvent was removed by a rotary evaporator and the residue was dried in vacuum giving compound 8 (347 mg) as a light yellow oil in quantitative yield. 1  Bis(E-2-bromo-1-ethyl-1-butenyl) selenide (9) was obtained under the same conditions as compound 8 but for 2 h from selenium dibromide and 3-hexyne as a light yellow oil in quantitative yield. 1  Bis(E-2-bromo-1-propyl-1-pentenyl) selenide (10) was obtained under the same conditions as compound 8 but for 2 h from selenium dibromide and 4-octyne as a light yellow oil in quantitative yield. 1  Bis(E-2-bromo-1-butyl-1-hexenyl) selenide (11) was obtained under the same conditions as compound 8 but for 3 h from selenium dibromide and 5-decyne as a light yellow oil in quantitative yield. 1 13